DESCRIPTION (Applicant's abstract): Physical activity represents one of the most potent physiological stimuli for angiogenesis (capillary proliferation) in muscle and arteriogenesis (enlargement of existing vessels) of collateral arteries that can benefit patients with peripheral arterial insufficiency. Our previous work, using a claudicate rat model produced by femoral artery occlusion, has shown that these adaptations improve muscle performance and increase collateral-dependent blood flow, the latter due to structural enlargement of collateral vessels. We now propose experiments to determine the mechanisms involved in collateral vessel expansion and microvascular proliferation, and the modulation of these processes by exercise and angiogenic growth factors. Unique approaches will evaluate: a) collateral vessel function and vasoreactivity in vitro, b) vascular signals contributing to collateral vessel arteriogenesis, and c) mechanisms controlling collateral blood flow increases in vivo. We will determine how vascular occlusion modifies affected collateral vessels to promote receptivity to arteriogenic stimuli, and how the dysfunction of collateral vessels is improved with exercise training and exogenous VEGF delivery. Adult rats are exercised by treadmill running. We will assess the means by which endothelial signaling of NO, alters regulation of VEGF and its receptors (VEGFR-1 and VEGFR-2), and the angiopoietins (Ang1 and Ang2, and their receptor Tie2) is modified to stimulate arteriogenesis in collateral vessels in vivo, using real-time rtPCR. NO, VEGF, Ang1, Ang2, and collateral flow demands will be experimentally managed to establish their interactions in controlling arteriogenesis and collateral blood flow increases following femoral artery occlusion. Collateral blood flow is determined during treadmill running in vivo. Further, we will evaluate the control of capillary proliferation induced by exercise and the functional impact of its absence in otherwise trained muscle. The outcome of these novel, physiologically relevant studies will enhance our understanding of vascular remodeling induced by physical activity and its applicability to managing patients with peripheral arterial insufficiency.